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Blood. 2015 Apr 23;125(17):2712-9. doi: 10.1182/blood-2014-11-611319. Epub 2015 Feb 17.

Arterial thrombosis is accelerated in mice deficient in histidine-rich glycoprotein.

Author information

1
Thrombosis and Atherosclerosis Research Institute, Department of Medical Sciences.
2
Thrombosis and Atherosclerosis Research Institute, Department of Medicine, and.
3
Helmholtz-Institute for Biomedical Engineering, Biointerface Laboratory, Rheinisch-Westfälische Technische Hochschule Aachen (RWTH) Aachen University, Aachen, Germany; and.
4
Isis Pharmaceuticals, Inc., Carlsbad, CA.
5
Thrombosis and Atherosclerosis Research Institute, Department of Medical Sciences, Department of Medicine, and.
6
Thrombosis and Atherosclerosis Research Institute, Department of Medical Sciences, Department of Medicine, and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada;

Abstract

Factor (F) XII, a key component of the contact system, triggers clotting via the intrinsic pathway, and is implicated in propagating thrombosis. Although nucleic acids are potent activators, it is unclear how the contact system is regulated to prevent uncontrolled clotting. Previously, we showed that histidine-rich glycoprotein (HRG) binds FXIIa and attenuates its capacity to trigger coagulation. To investigate the role of HRG as a regulator of the intrinsic pathway, we compared RNA- and DNA-induced thrombin generation in plasma from HRG-deficient and wild-type mice. Thrombin generation was enhanced in plasma from HRG-deficient mice, and accelerated clotting was restored to normal with HRG reconstitution. Although blood loss after tail tip amputation was similar in HRG-deficient and wild-type mice, carotid artery occlusion after FeCl3 injury was accelerated in HRG-deficient mice, and HRG administration abrogated this effect. To confirm that HRG modulates the contact system, we used DNase, RNase, and antisense oligonucleotides to characterize the FeCl3 model. Whereas DNase or FVII knockdown had no effect, carotid occlusion was abrogated with RNase or FXII knockdown, confirming that FeCl3-induced thrombosis is triggered by RNA in a FXII-dependent fashion. Therefore, in a nucleic acid-driven model, HRG inhibits thrombosis by modulating the intrinsic pathway of coagulation.

PMID:
25691157
PMCID:
PMC4416941
DOI:
10.1182/blood-2014-11-611319
[Indexed for MEDLINE]
Free PMC Article

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